METABOLIC PROCESSES FOR CALCIUM ENTRY ANTAGONISTS

钙进入拮抗剂的代谢过程

• 批准号: 3346613
• 负责人: Wendel L. Nelson
• 金额: $ 11.81万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-04-01 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3346613
• 关键词: alkylation; calcium channel blockers; carbonyl compound; cyanides; drug metabolism; mass spectrometry; membrane permeability; microsomes; racemization; stereoisomer; verapamil

The aims of this proposal are related to chemical and stereochemical aspects of metabolic processes that occur in two important slow calcium channel antagonists verapamil and D-600. Work is proposed which will delineate pathways of metabolite formation and provide a source of the enantiomers of these compounds to facilitate pharmacogical studies and studies on stereoselectivity of the metabolic processes. Structures of metabolites of verapamil and of D-600 will be determined by GC-MS comparison with standards of known structure. Stereoselectivity of metabolic processes will be studied using pseudoracemic mixtures of the enantiomers of verapamil and D-600. A suitable deuterium labeling procedure that is readily applicable to the individual enantiomers without racemization has been found. Deuterium labeling and use of pseudoracemic substrates will facilitate determination of metabolites arising from dealkylation of either the longer or short side chain. Mechanistic aspects of the N-dealkylation process will be examined on verapamil by determining carbonyl compounds and iminium ions which arise by metabolic N-dealkylation. Specifically deuterated verapamil will also be used to determine whether an equilibrium exists between iminium ions. Methods for the analysis of individual enantiomers of verapamil and D-600 will be explored to determine whether it is possible to determine the individual enatiomers from samples containing racemic (non-pseudoracemic) compound. Diastereomeric derivatization will be performed on reduction products of verapamil and D-600.

该提案的目的与化学和立体化学有关 在两个重要的慢钙中发生的代谢过程的各个方面 通道拮抗剂维拉帕米和D-600。 提出了工作 描绘代谢产物形成的途径，并提供 这些化合物的对映异构体，以促进药物研究和 关于代谢过程的立体选择性的研究。 Verapamil和D-600代谢物的结构将由 GC-MS与已知结构标准的比较。 立体选择性 代谢过程将使用伪学的混合物进行研究 Verapamil和D-600的对映异构体。 合适的氘标记 容易适用于单个对映异构体的程序 已经发现了种族化。 氘标记和使用伪虫学 底物将促进确定由 较长或短侧链的交易。 机械方面 通过确定，将在Verapamil上检查N-脱甲基化过程 代谢产生的羰基化合物和亚米胺离子 n-脱烷基化。 具体剥离的维拉帕米也将用于 确定在亚米亚离子之间是否存在平衡。 方法 Verapamil和D-600的各个对映异构体的分析将是 探索以确定是否可以确定个人 来自含有外消毒（非育种）化合物的样品中的enatiomers。 非对非易非洲映称组合衍生化将在还原产物的减少产物上进行 Verapamil和D-600。